1. Field of the Invention
The present invention relates to a low flow rate nebulization method and a low flow rate nebulizer apparatus used in respiratory care and, in particular, to a continuously connected, continuous low gas flow rate liquid nebulizer useful in respiratory care to deliver liquid medications.
2. Description of the Related Art
Crtically ill patients requiring mechanical ventilation are often victims of respiratory distress syndrome, status asthamaticus and pulmonary infections. Treatment of these and other severe respiratory conditions includes medications delivered directly to the lungs of the patient.
Respiratory delivery of medication for these conditions is preferable to oral, intravenous and subcutaneous delivery because it is non-invasive, permits rapid action of medicament, requires a relatively small dosage, is not filtered through the liver of the patient, and produces a low incidence of systemic side effects.
Nebulized or aerosolized solutions are the preferred method of respiratory delivery of medication; when fragmented into small particles, medicants are more efficiently deposited near sites of medicant activity in the lung.
Respiratory medications may be delivered to the lungs of the patient as an aerosol of a liquid or a powder. Clinical aerosols are currently generated by jet or ulrasonic nebulizers, metered dose inhalers (MDI) and dry powdered inhalers.
Liquid nebulizers are well known in the art. Aerosolization of liquid medications is preformed by putting a liquid product in a chamber (nebulizer vial) that has a pressurized flow of gas through it. Utilizing the Bernoulli principle, liquid is drawn through an aspirator tube into the path of a high velocity gas and is fractured into a mist. The mist flows out of the nebulizer by inertial forces.
There are two principal types of nebulizers for the delivery of liquid medication to the lungs: jet nebulizers and ultrasonic nebulizers. In conventional jet nebulizers, compressed gas from a compressor or hospital air line is passed through a narrow constriction known as a jet. This creates an area of low pressure, and liquid medication from a reservoir is drawn up through a feed tube and fragmented into droplets by the airstream. Only the smallest drops leave the nebulizer directly, while the majority impact on baffles and walls and are returned to the reservoior. Consequently, jet nebulization takes several minutes to complete, depending upon the initial volume.
Important disadvantages of nebulizers include low lung deposition related to the use of tidal breathing. A substantial portion of the dose used in a jet nebulizer is retained permanently as a dead or residual volume on baffles and internal walls of the nebulizer chamber and cannot be released. Generally only 2-10% of the dose placed in the nebulizer ever reaches the lung. The consequences are a higher drug dosage and longer administrative time, along with the associated cost and risk of contamination.
Current conventional liquid aerosol drug therapy involves administering a finite quantity (dose) of liquid medication deposited into the nebulizer vial and administered until the vial is empty. In normal practice, the period of delivery of each dose is measured in minutes or fractions of an hour. Depending upon the severity of the illness and the duration of activity of the medication, this process is repeated periodically at variable frequencies.
Such intermittent drug administration has the inherent results of (1) subjecting the patient to "peaks and "valleys" of drug dosage effects, (2) requiring respiratory therapy personnel to periodically service the needs of the patient and nebulizer by measuring doses, disconnecting, filling and reconnecting the nebulizer and periodically monitoring the administration, and (3) disconnecting the patient from an attached ventilator during nebulizer service. Further, medication which is administered as a large volume, such as a surfactant, now requires large medicant flow volume through the nebulizer requiring frequent servicing and refilling of the nebulizer vial which interferes with ventilator function.
In some cases, a significant proportion of the respiratory flow to the patient is through the nebulizer such as in the operational use of the VISAN nebulizer of Burroughs Wellcome Company. In the delivery of the medicant EXOSURF.RTM. surfactant, up to half of the tidal volume flows through the nebulizing ports of the nebulizer to unite with the balance of the respiratory gas delivered directly from the ventilator in a Y-shaped junction in the flow path to the patient downstream from the nebulizer. In such delivery, the nebulizing gas is synchronized with the nebulizer such that nebulizing gas is delivered to the nebulizer only during the ventilatory inhalation cycle.
A nebulizer comprising a vial-like nebulizing chamber which comprises a two-position flow control valve assembly for accessibly draining and refilling the nebulizing chamber is disclosed in U.S. Pat. No. 4,805,609. While the valve assembly provides access for resupplying a medication close while the nebulizing chamber remains in sealed relation with the nebulizer, such resupply is service intensive and limited to volumes containable by the nebulizing chamber.
Recent developments in respiration therapy involve aersolization and delivery of nebulized mist on a continuous basis over several hours. For example, an entire day's medication dosage is delivered at a constant rate over twenty-four hours, as opposed to conventionally delivering the same dosage as four separate aliquots at six hour intervals. Such delivery eliminates the "peak" and "valleys" effects of the drug, reduces respiratory personnel suport times, and also reduces the number of time critical medication/nebulizer interconnections are interrupted, thereby diminishing the potentially dangerous exposures of the patient to the effects of respiratory circuit contamination.
Delivery of medicated mist is both in combination with a ventilator and through masks, mouthpieces, and other voluntary mist inhalation apparatus.
The second type of aerosol generator is a metered dose inhalator (MDI), which delivers a bolus of more concentrated drug aerosols than the solution commonly available for nebulizers. For optimal effect, MDI delivery systems require proper administration technique, which includes coordinated actuation of aerosol delivery with inhalation, a slow inhalation of 0.5-0.75 liters per second, a deep breath approaching inspiratory capacity inhalation, and at least 4 seconds of breath holding.
Many patients find it difficult to properly administer medication with an MDI, especially during acute exorbation. An article which appeared in Eur. J. Respit. Dis., 68(5), 332 (1986), entitled "Bronchodilator Effects of a Fenoterol Meter Dose Inhaler and Fenoterol Powder in Asthmatics with Poor Inhaler Technique," described test findings showing that the effectiveness of bronchodilator medication, when delivered with an MDI, is dependent on good MDI technique. The article suggested that delivery of medication in a powdered form is more reliable for patients who do not exercise proper MDI technique.
MDIs can be equipped with devices that automatically couple actuation to inspiratory effort, thus eliminating the need for coordinating hand action with inhalation. Devices such as spacers and holding chambers also decrease partial velocity and reduce the number of large particles. Both of these features reduce oral pharyngeal and large airway deposition with a consequent reduction in systemic absorption. Deposition of aerosols from an MDI with a spacer or holding chamber is similar and perhaps better than the deposition of a properly used MDI alone.
Advantages of the MDI include deposition of 10-15% of the metered dose with consequent short treatment time, low cost and increased convenience. However, MDIs cannot be used by patients requiring mechanical ventilation. Other disadvantages include the need for patient cooperation, the practical limitations and inconveniences associated with increased dosing requirements due to the typically small dosages administered with an MDI, the limited number of currently available drugs, and the dependence on fluorocarbons of aerosol generation.
Others have recognized the need for new inhalation devices such as modified dry powder inhalers to replace use of MDIs due to environmental concerns related to the use of fluorocarbons. See "Today's Treatment of Airway Obstruction . . . and Tomorrow's?" Flenley, D. C., Respiration, 55 Suppl. 2, 4 (1989).
The third type of aerosol generator is a dry powder inhaler. Dry powdered inhalation devices currently in use are the Spinbaler, the Rotahaler, the Turbohaler and the disc inhaler. Dry powdered inhalers are breath actuated and usually require a higher inspiratory flow rate than that required for an MDI or a nebulizer. Flow rates of 1-2 liters per second are usually considered optimal, although flow rates as low as 0.5 liters per second may be effective for some dry powdered inhalers.
Advantages of dry powdered inhalers include relative ease of administration and the fact that they do not require fluorocarbon propellants. When a dry powdered inhaler is used properly, deposition appears to be similar to that of a properly used MDI.
However, powdered inhalers are limited by the dose they can provide and by the number of drugs currently available. Only terbutaline, salbutamol, dexamethasone and chromolyn sodium are available in powder form.
All conventional powder inhaler delivery systems utilize single dose capsules except the Turbohaler for administration of terbutaline. While several devices have been developed which permit preloading of several single dose capsules, neither these devices nor the Turbohaler have eliminated the other disadvantages of conventional powdered inhalers. See "A New Inhalation System for Bronchodilation. Study of the Acceptance of the Ingelheim M Inhaler in Chronic Obstructive Respiratory Tract Disease." Mutterlein, B. Schmidt, B., Fleisher, W., and Freund, D., Fortschr. Med., April 15, 108(11), 225 (1990); "In Vivo Evaluation of the New Multiple Dose Powder Inhaler and the Rotahaler Using the Gamma Scintigraphy," Vidaren, M., Paronen, P., Vidaren, P. Vainir, P., and Nuutinen, J., Acta. Pharm. Nord., 2(1), 3 (1990); "Clinical Use of Dry Powder Systems," Crompton, G. K., Eur. J. Respir. Dis. Suppl., 122, 96 (1962).
Other disadvantages of dry powdered inhalers include the following: a) they are usually not particle size-selective and thus heavy oral pharyngeal deposition may occur; b) high humidity environments may cause clumping of the particles; and c) dry powdered inhalers cannot be used in ventilatory circuits.
Currently available devices for delivery of powdered medications to respiratory therapy do not employ nebulization technology.
The use of compressed air powered jet mills as a power generator for inhalation experiments is disclosed in "Use of a Jet Mill for Dispersing Dry Powder for Inhalation Studies," Cheng, Y. S., Marshall, T. C., Henderson, R. R., and Newton, G. J., Am. Ind. Hya. Assoc. J., 46(8), 449 (1985). The jet mill consisted of an elongated channel), one material delivery jet, and two high speed air jets. Powder fed into the channel was dispersed by turbulence and centrifugal forces. The powder used in the inhalation experiments consisted of dye materials to be tested for toxicity. A flow rate of 400 liters per minute was maintained. The article does not address nebulization of powdered medication for purposes of respiratory therapy.
U.S. Pat. No. 4,232,002 discloses procedures for administering antihistamines. Methods disclosed include inhalation by a patient of mist, nebulized spray, or a cloud of fine solid particles. Products for delivery of medication include pressurized canistor inhalers, portable dry powder insuffilators using capsules, and nebulizers. The only dry powder delivery system described is a dry powder inhaler using capsules of dry powder in single dose units. The delivery method described involves puncturing a capsule of dry powder medication which is dispersed by means of a turbomixer to be inhaled thorugh a mouth piece. This patent does not address continuous flow or continuous delivery of inhalable medication. It does not enablingly teach or address jet nebulization of powdered solid medications, and does not teach a nebulizer vial which connects to a nebulizer to provide a device for introducing continuous flow.
U.S. Pat. No. 3,669,113 discloses a method and device for dispensing powdered medication from a perforated container by rotating the container by pneumatic means and causing the axis of rotation of the container to precess and describe a path of precession which is contained within a generally conical surface of a precession. The mechanisms described are based on varying shaft and bearing configurations. The method of this patent is said to be especially well suited to delivery of particles less than 80 microns in diameter. The patent does not address jet nebulization, continuous flow or continuous nebulization.
Recent developments in respiration therapy involve aerosolization and delivery of nebulized liquids on a continuous basis over several hours. Such delivery stabilizes the effects of the medication over time, reduces respiratory personnel support time, and reduces the chances of respiratory circuit contamination.
In our prior co-pending U.S. patent application Ser. No. 07/729,518, filed Jul. 12, 1991, a liquid nebulizer system is disclosed comprising a nebulizer attachable nebulizer vial, a large supply vessel, and a fluid delivery system, to be used with a conventional liquid nebulizer. The liquid nebulizer system provides for continuous delivery of liquid medication from a large supply vessel into the nebulizer vial which is attached to a conventional nebulizing apparatus, permitting continuous delivery of nebulized liquid medication. The disclosure of such prior copending application is hereby incorporated herein by reference.
In conventional, commercially available liquid nebulizer systems, a carrier gas flow rate in the range of from about 6 to about 8 liters per minute is used. Such flow rate range is necessary for conventional nebulizer devices to operate with suitable efficiency, but such relatively large flow rates also lead to substantial loss and wasteage of the nebulized drug, due primarily to the fact that the flow rates in such range exceed the patient uptake rate on a continuous basis.
It is possible to reduce carrier gas flow rate below such 6-8 liter per minute range, but at such lower flow rates, nebulization efficiency becomes disproportionately poorer as the flow rate is reduced to levels as low as 4-5 liters per minute, with the result that a carrier gas flow rate of 4 liters per minute is considered a conventional "low flow" regime defining the limits of operability of commercially available liquid nebulizer devices.
Further, even at such "low flow" conditions on the order of 4-5 liters per minute, the tidal volume respiratory gas is substantially larger than lung capacity for neonatal patients and others with reduced lung capacity such as patients who possess only one lung. At low flow rates, on the order of 4-5 liters per minute, the nebulization efficiency becomes unsuitable since the gas flow rate is not adequate to produce a usefully fine particle size distribution of the medicant.
Accordingly, where low flow delivery of medicant materials is required, the only practical device is an ultrasonic nozzle. However, ultrasonic nozzles suffer the deficiencies that they are costly, tend to denature a variety of otherwise useful drugs which in denatured form are non-efficacious, and ultrasonic nozzles tend to have a short operating life, due to nozzle wear and degradation.
It would therefore be highly desirable to provide a liquid nebulizer device which is usefully employed to deliver medicant materials in a carrier gas flow stream at a flow rate substantially below the range of 4-5 liters per minute, which is the practical lower limit with conventional nebulizer apparatus.
Accordingly, it is an object of the present invention to provide such a liquid nebulizer system capable of operating at carrier gas flow rates substantially below the 4-5 liter per minute practical lower limit of currently available commercial nebulizer devices.
It is another object of the present invention to provide a nebulization system of such type which may be used for delivery of liquid as well as solid medicaments.
It is a further object of the present invention to provide a method and apparatus for continuous respiratory delivery by low flow rate gas nebulization of liquid medicaments.
It is still another object of the present invention to provide a method and apparatus for respiratory delivery of low gas flow nebulization of liquid medication which may be used in ventilatory circuits.
It is yet another object of the invention to provide a method and apparatus which overcome the disadvantages associated with currently available respiratory medicant delivery systems.
These and other objects and advantages of the present invention will be more fuly apparent from the ensuing disclosure and appended claims.